Succinate Metabolism in Cancer Biology

Succinate stands at the nexus of mitochondrial bioenergetics and cellular signalling. Within the tricarboxylic acid (TCA) cycle, succinate is produced by the oxidation of succinyl-CoA and subsequently oxidised by succinate dehydrogenase (Complex II) in the inner mitochondrial membrane. In many cancers, mutations or downregulation of succinate dehydrogenase subunits lead to succinate accumulation, which inhibits α-ketoglutarate-dependent dioxygenases, stabilises hypoxia-inducible factors and induces epigenetic remodelling characteristic of a pseudohypoxic state. Excess succinate can be exported via monocarboxylate transporters and engage SUCNR1 on tumour, stromal and immune cells, promoting angiogenesis, inflammatory cell recruitment and extracellular matrix remodelling. Tumours also exploit amino acid catabolism, such as valine degradation, to anaplerotically refill the TCA cycle succinate pool and sustain anabolic growth. By acting both as an oncometabolite and a paracrine signal, succinate integrates metabolic rewiring with microenvironmental crosstalk to drive cancer progression.

Research from Nature Portfolio

Recent studies have elucidated how Complex II assembly modulates succinate turnover. Structural and biochemical analyses identified metastable intermediates of the SDHA subunit bound to assembly factors. Intrinsically disordered regions in these factors undergo transitions that govern Complex II maturation, revealing regulatory checkpoints that may influence succinate oxidation in tumour cells.

In hepatocellular carcinoma, reduced expression of the SDHB subunit was linked to advanced tumour stage and poor patient survival. Functional silencing of SDHB in cell lines and xenograft models triggered a metabolic switch from oxidative phosphorylation to aerobic glycolysis, enhancing proliferation, motility and metastatic potential. Restoration of SDHB expression reversed these malignant features, confirming its role in restraining the Warburg effect and tumour aggressiveness.

Succinate Metabolism in Cancer Biology publication trend

The graph below shows the total number of articles in succinate metabolism in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Succinate dehydrogenase (SDH; Complex II): A mitochondrial enzyme complex that oxidises succinate to fumarate and transfers electrons to the respiratory chain.

Oncometabolite: A metabolic intermediate whose accumulation disrupts normal cellular regulation and promotes tumourigenesis.

SUCNR1 (GPR91): A G-protein-coupled receptor for extracellular succinate that mediates paracrine signalling in various cell types.

Anaplerosis: The process of replenishing TCA cycle intermediates to support bioenergetic and biosynthetic demands.

References

1. Disordered-to-ordered transitions in assembly factors allow the complex II catalytic subunit to switch binding partners. Nature Communications (2024).
2. Decreased succinate dehydrogenase B in human hepatocellular carcinoma accelerates tumor malignancy by inducing the Warburg effect. Scientific Reports (2018).
3. Targeting valine catabolism to inhibit metabolic reprogramming in prostate cancer. Cell Death & Disease (2024).
4. Oncometabolite succinate promotes angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation. Oncotarget (2017).